Bicyclic heterocyclic derivatives

ABSTRACT

in which X, Y, R1 and R2 have the meanings indicated in claim 1, are inhibitors of pyruvate dehydrogenase kinase (PDHK), and can be employed, inter alia, for the treatment of diseases such as cancer.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel bicyclic heterocyclic derivativeswhich inhibit pyruvate dehydrogenase kinase (PDHK), to pharmaceuticalcompositions comprising them, to processes for their preparation, and totheir use in therapy for the treatment of cancers.

BACKGROUND OF THE INVENTION

Pyruvate dehydrogenase kinase (also pyruvate dehydrogenase complexkinase, PDC kinase, or PDHK) is a kinase enzyme which acts to inactivatethe enzyme pyruvate dehydrogenase by phosphorylating it using ATP.

PDHK thus participates in the regulation of the pyruvate dehydrogenasecomplex of which pyruvate dehydrogenase is the first component. BothPDHK and the pyruvate dehydrogenase complex are located in themitochondrial matrix of eukaryotes. The complex acts to convert pyruvate(a product of glycolysis in the cytosol) to acetyl-coA, which is thenoxidized in the mitochondria to produce energy, in the citric acidcycle. By downregulating the activity of this complex, PDHK willdecrease the oxidation of pyruvate in mitochondria and increase theconversion of pyruvate to lactate in the cytosol.

The opposite action of PDHK, namely the dephosphorylation and activationof pyruvate dehydrogenase, is catalyzed by a phosphoprotein phosphatasecalled pyruvate dehydrogenase phosphatase.

(Pyruvate dehydrogenase kinase should not be confused withPhosphoinositide-dependent kinase-1, which is also sometimes known as“PDK1”.)

There are four known isozymes of PDHK in humans: PDHK1-PDHK4.

Some studies have shown that cells that lack insulin (or are insensitiveto insulin) overexpress PDHK4. As a result, the pyruvate formed fromglycolysis cannot be oxidized which leads to hyperglycaemia due to thefact that glucose in the blood cannot be used efficiently. Thereforeseveral drugs target PDHK4 hoping to treat type II diabetes.

PDHK1 has shown to have increased activity in hypoxic cancer cells dueto the presence of HIF-1. PDHK1 shunts pyruvate away from the citricacid cycle and keeps the hypoxic cell alive. Therefore, PDHK1 inhibitionhas been suggested as an antitumor therapy since PDHK1 preventsapoptosis in these cancerous cells. Similarly, PDHK3 has been shown tobe overexpressed in colon cancer cell lines. Three proposed inhibitorsare AZD7545 and dichloroacetate which both bind to PDHK1, and Radicicolwhich binds to PDHK3.

Increasing PDC in the active form by inhibiting PDHK activity is a drugtarget for diabetes, heart disease and cancer.

EP 2 345 629 A1 discloses PDHK inhibitors which are considered to beuseful for the treatment or prophylaxis of diseases relating to glucoseutilization disorder, for example, diabetes (e.g., type 1 diabetes, type2 diabetes etc.), insulin resistance syndrome, metabolic syndrome,hyperglycemia and hyperlactacidemia. In addition, a PDHK inhibitor isconsidered to be useful for the treatment or prophylaxis of diabeticcomplications (e.g., neuropathy, retinopathy, nephropathy, cataractetc.). Furthermore, a PDHK inhibitor is considered to be useful for thetreatment or prophylaxis of diseases caused by limited energy substratesupply to the tissues, for example, cardiac failure, cardiomyopathy,myocardial ischemia, dyslipidemia and atherosclerosis. Additionally, aPDHK inhibitor is considered to be useful for the treatment orprophylaxis of cerebral ischemia or cerebral apoplexy. Moreover, a PDHKinhibitor is considered to be useful for the treatment or prophylaxis ofmitochondrial disease, mitochondrial encephalomyopathy, cancer and thelike.

Also, it is considered to be useful for the treatment or prophylaxis ofpulmonary hypertension.

LITERATURE

Wikipedia, pyruvate dehydrogenase kinase;

-   T. E. Roche et al., Cell. Mol. Life Sci. 64 (2007) 830-849;-   A. Kumar et al., Chemico-Biological Interactions 199 (2012) 29-37;-   I. Papandreou et al., Int. J. Cancer: 128, 1001-1008 (2011);-   G. Sutendra et al., frontiers in oncology, 2013, vol. 3, 1-11.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The present invention specifically relates to compounds of the formulaIa or Ib which inhibit PDHK, preferably PDHK2, to compositions whichcomprise these compounds, and to processes for the use thereof for thetreatment of PDHK-induced diseases and complaints.

The compounds of the formula Ia or Ib can furthermore be used for theisolation and investigation of the activity or expression of PDHK. Inaddition, they are particularly suitable for use in diagnostic methodsfor diseases in connection with unregulated or disturbed PDHK activity.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow active agents such as anti IgM to induce a cellularresponse such as expression of a surface marker, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from blood or from a biopsy sample. The amount ofsurface marker expressed is assessed by flow cytometry using specificantibodies recognising the marker.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

PRIOR ART

Bicylic pyrazolo-heterocyclic derivatives for the treatment of pain andinflammation are described in WO 2010/088050.

Other bicyclic heterocyclic compounds as protein kinase inhibitors aredescribed in WO 2009/143477.

Other pyrazolopyridines for the treatment of inflammations are describedin U.S. Pat. No. 3,423,414.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula Ia or of the formulaIb

-   in which-   X denotes CH or N,-   Y denotes CH or N,-   R¹ denotes H, A, (CH₂)_(n)Ar, (CH₂)_(n)Het or Cyc,-   R² denotes H or CH₃,-   Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,    tetra- or pentasubstituted by Hal, A, CN, OA, [C(R⁵)₂]_(p)OH,    [C(R⁵)₂]_(p)N(R⁵)₂, NO₂, [C(R⁵)₂]_(p)COOR⁵, NR⁵COA, NR⁵SO₂A,    [C(R⁵)₂]_(p)SO₂N(R⁵)₂, S(O)_(n)A, O[C(R⁵)₂]_(m)N(R⁵)₂, NR⁵COOA,    NR⁵CON(R⁵)₂ and/or COA,

Het denotes a mono- or bicyclic saturated, unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted ormono- or disubstituted by Hal, A, CN, OA, [C(R⁵)₂]_(p)OH,[C(R⁵)₂]_(p)N(R⁵)₂, NO₂, [C(R⁵)₂]_(p)COOR⁵, NR⁵COA, NR⁵SO₂A,[C(R⁵)₂]_(p)SO₂N(R⁵)₂, S(O)_(n)A, O[C(R⁵)₂]_(m)N(R⁵)₂, NR⁵COOA,NR⁵CON(R⁵)₂ and/or COA,

-   Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, which is    unsubstituted or monosubstituted by OH,-   A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein    one or two non-adjacent CH- and/or CH₂-groups may be replaced by N-,    O- and/or S-atoms and/or wherein 1-7 H-atoms may be replaced by R⁴,-   R⁴ denotes F, Cl or OH,-   R⁵ denotes H oder A′,-   A′ denotes unbranched or branched alkyl with 1-6 C-atoms, wherein    1-5 H-atoms may be replaced by F,-   Hal denotes F, Cl, Br or I,-   m denotes 1, 2, 3 or 4,-   n denotes 0, 1 or 2,-   p denotes 0, 1, 2, 3 or 4,-   with the proviso that,-   if X═CH then Y═N-   or-   if Y═CH then X═N,-   and pharmaceutically acceptable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds.

Moreover, the invention relates to pharmaceutically acceptablederivatives of compounds of formula Ia or Ib.

The term solvates of the compounds is taken to mean adductions of inertsolvent molecules onto the compounds which form owing to their mutualattractive force. Solvates are, for example, mono- or dihydrates oralkoxides. It is understood, that the invention also relates to thesolvates of the salts.

The term pharmaceutically acceptable derivatives is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound of formula Ia or Ib that can hydrolyze,oxidize, or otherwise react under biological conditions (in vitro or invivo) to provide an active compound, particularly a compound of formulaIa or Ib. Examples of prodrugs include, but are not limited to,derivatives and metabolites of a compound of formula Ia or Ib thatinclude biohydrolyzable moieties such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues. In certain embodiments, prodrugs of compounds with carboxylfunctional groups are the lower alkyl esters of the carboxylic acid. Thecarboxylate esters are conveniently formed by esterifying any of thecarboxylic acid moieties present on the molecule. Prodrugs can typicallybe prepared using well-known methods, such as those described byBurger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J.Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula Ia or Ib, for example mixtures of two diastereomers, forexample in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution.

The invention relates to the compounds of the formula Ia or Ib and saltsthereof and to a process for the preparation of compounds of the formulaIa or Ib and pharmaceutically acceptable salts, solvates, tautomers andstereoisomers thereof characterised in that a compound of the formulaIIa or IIb

-   -   in which X, Y, R¹ and R² have the meanings indicated in claim 1,

is reacted with a compound of the formula Ill

-   -   in which L denotes Cl, Br, I or a free or reactively        functionally modified OH group,

and/or

a base or acid of the formula I is converted into one of its salts.

Above and below, the radicals X, Y, R¹ and R² have the meaningsindicated for the formula Ia or Ib, unless expressly stated otherwise.

A denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A preferably denotes unbranched or branched alkyl with 1-10 C-atoms,wherein one or two non-adjacent CH- and/or CH₂-groups may be replaced byN- and/or O-atoms and wherein 1-7 H-atoms may be replaced by R⁴.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl. Moreover, A denotes preferably CH₂OCH₃,CH₂CH₂OH or CH₂CH₂OCH₃. Cyc denotes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl, preferably unsubstituted ormonosubstituted by OH.

A′ denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5 or 6 C atoms. A′ preferably denotes methyl, furthermore ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermorealso pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A′ very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6C atoms, wherein 1-3 H-atoms may be replaced by F.

Ar denotes preferably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl,o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonyl-phenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethyl-aminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methyl-sulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-carboxyphenyl, o-, m- orp-methoxycarbonylphenyl, o-, m- or p-acetylphenyl, o-, m- orp-amino-sulfonylphenyl, o-, m- or p-[2-(morpholin-4-yl)ethoxy]phenyl,o-, m- or p-[3-(N,N-diethylamino)propoxy]phenyl, furthermore preferably2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar furthermore preferably denotes phenyl, which is unsubstituted ormono-, di-, tri-, tetra- or pentasubstituted by Hal, A, CN and/or OA.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4-, -5-yl or2,1,3-benzoxadiazol-5-yl, azabicyclo[3.2.1]octyl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Irrespective of further substitutions, Het can thus also denote, forexample, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl,piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl orthiadiazolyl, each of which is unsubstituted or mono- or disubstitutedby Hal, A and/or OA.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula Ia or Ib may have one or more chiralcentres and can therefore occur in various stereoisomeric forms. Theformula Ia or Ib encompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula Ia or Ib in which at least one of the said radicals has oneof the preferred meanings indicated above. Some preferred groups ofcompounds may be expressed by the following sub-formulae Iaa to Iac,which conform to the formula Ia or Ib and in which the radicals notdesignated in greater detail have the meaning indicated for the formulaIa or Ib, but in which

-   in Iaa Ar denotes phenyl, which is unsubstituted or mono-, di-,    tri-, tetra- or pentasubstituted by Hal, A, CN and/or OA;-   in Iab Het denotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl,    piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl,    furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,    oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono-    or disubstituted by Hal, A and/or OA;-   in Iac X denotes CH or N,    -   Y denotes CH or N,    -   R¹ denotes H, A, (CH₂)_(n)Ar, (CH₂)_(n)Het or Cyc,    -   R² denotes H or CH₃,    -   Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,        tetra- or pentasubstituted by Hal, A, CN and/or OA,    -   Het denotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl,        piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl,        furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,        oxadiazolyl or thiadiazolyl, each of which is unsubstituted or        mono- or disubstituted by Hal, A and/or OA,    -   Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, which is        unsubstituted or monosubstituted by OH,    -   A denotes unbranched or branched alkyl with 1-10 C-atoms,        wherein one or two non-adjacent CH- and/or CH₂-groups may be        replaced by N-, O- and/or S-atoms and/or wherein 1-7 H-atoms may        be replaced by R⁴,    -   R⁴ denotes F, Cl or OH,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1 or 2,    -   with the proviso that,    -   if X═CH then Y═N    -   ord    -   if Y═CH then X═N,

and pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.

The compounds of the formula Ia or Ib and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The starting compounds for the preparation of compounds of formula Ia orIb are generally known. If they are novel, however, they can be preparedby methods known per se.

Compounds of the formula Ia or Ib can preferably be obtained by reactinga compound of the formula IIa or IIb, with a compound of the formulaIII.

In the compounds of the formula III, L preferably denotes Cl, Br, I or afree or reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethyl-sulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethyl-aniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Preferably the reaction is carried out in the presence of[Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluoro phosphate [HATU; coupling reagent] or in the presence of1-chloro-N,N,2-trimethyl-1-propenylamine.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon di-sulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to acetonitrile, dichloromethane and/orDMF.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formulaIa or Ib are for the most part prepared by conventional methods. If thecompound of the formula Ia or Ib contains a carboxyl group, one of itssuitable salts can be formed by reacting the compound with a suitablebase to give the corresponding base-addition salt. Such bases are, forexample, alkali metal hydroxides, including potassium hydroxide, sodiumhydroxide and lithium hydroxide; alkaline earth metal hydroxides, suchas barium hydroxide and calcium hydroxide; alkali metal alkoxides, forexample potassium ethoxide and sodium propoxide; and various organicbases, such as piperidine, diethanolamine and N-methylglutamine. Thealuminium salts of the compounds of the formula Ia or Ib are likewiseincluded. In the case of certain compounds of the formula Ia or Ib,acid-addition salts can be formed by treating these compounds withpharmaceutically acceptable organic and inorganic acids, for examplehydrogen halides, such as hydrogen chloride, hydrogen bromide orhydrogen iodide, other mineral acids and corresponding salts thereof,such as sulfate, nitrate or phosphate and the like, and alkyl- andmonoarylsulfonates, such as ethanesulfonate, toluenesulfonate andbenzene-sulfonate, and other organic acids and corresponding saltsthereof, such as acetate, trifluoroacetate, tartrate, maleate,succinate, citrate, benzoate, salicylate, ascorbate and the like.Accordingly, pharmaceutically acceptable acid-addition salts of thecompounds of the formula Ia or Ib include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzene-sulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentane-propionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecyl-sulfate, ethanesulfonate, fumarate, formate,galacterate (from mucic acid), galacturonate, glucoheptanoate,gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate,iso-butyrate, lactate, lactobionate, malate, maleate, malonate,mandelate, metaphosphate, methanesulfonate, methylbenzoate,monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,3-phenylpropionate, phosphate, phosphonate, phthalate, but this does notrepresent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula Ia or Ib which arederived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary and tertiary amines, substituted amines,also including naturally occurring substituted amines, cyclic amines,and basic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula Ia or Ib areprepared by bringing the free base form into contact with a sufficientamount of the desired acid, causing the formation of the salt in aconventional manner. The free base can be regenerated by bringing thesalt form into contact with a base and isolating the free base in aconventional manner. The free base forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula Ia or Ib are formed with metals or amines, suchas alkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula Iaor Ib in the form of one of its salts, in particular if this salt formimparts improved pharmacokinetic properties on the active ingredientcompared with the free form of the active ingredient or any other saltform of the active ingredient used earlier.

The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

Isotopes

There is furthermore intended that a compound of the formula Ia or Ibincludes isotope-labelled forms thereof. An isotope-labelled form of acompound of the formula Ia or Ib is identical to this compound apartfrom the fact that one or more atoms of the compound have been replacedby an atom or atoms having an atomic mass or mass number which differsfrom the atomic mass or mass number of the atom which usually occursnaturally. Examples of isotopes which are readily commercially availableand which can be incorporated into a compound of the formula I bywell-known methods include isotopes of hydrogen, carbon, nitrogen,oxygen, phos-phorus, fluorine and chlorine, for example ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Acompound of the formula Ia or Ib, a prodrug, thereof or apharmaceutically acceptable salt of either which contains one or more ofthe above-mentioned isotopes and/or other isotopes of other atoms isintended to be part of the present invention. An isotope-labelledcompound of the formula Ia or Ib can be used in a number of beneficialways. For example, an isotope-labelled compound of the formula Ia or Ibinto which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula Ia or Ib hastherapeutic advantages owing to the higher metabolic stability of thisisotope-labelled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder most circumstances would represent a preferred embodi-ment of thepresent invention. An isotope-labelled compound of the formula Ia or Ibcan usually be prepared by carrying out the procedures dis-closed in thesynthesis schemes and the related description, in the example part andin the preparation part in the present text, replacing anon-isotope-labelled reactant by a readily available isotope-labelledreactant.

Deuterium (²H) can also be incorporated into a compound of the formulaIa or Ib for the purpose in order to manipulate the oxidative metabolismof the compound by way of the primary kinetic isotope effect. Theprimary kinetic isotope effect is a change of the rate for a chemicalreaction that results from exchange of isotopic nuclei, which in turn iscaused by the change in ground state energies necessary for covalentbond formation after this isotopic exchange. Exchange of a heavierisotope usually results in a lowering of the ground state energy for achemical bond and thus cause a reduction in the rate in rate-limitingbond breakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a compoundof the formula Ia or Ib that is susceptible to oxidation, the profile ofthis compound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula Ia or Ib with improved stabilitythrough resistance to such oxidative metabolism. Significantimprovements in the pharmacokinetic profiles of compounds of the formulaIa or Ib are thereby obtained, and can be expressed quantitatively interms of increases in the in vivo half-life (t½), concentration atmaximum therapeutic effect (C_(max)), area under the dose response curve(AUC), and F; and in terms of reduced clearance, dose and materialscosts.

The following is intended to illustrate the above: a compound of theformula Ia or Ib which has multiple potential sites of attack foroxidative metabolism, for example benzylic hydrogen atoms and hydrogenatoms bonded to a nitrogen atom, is prepared as a series of analogues inwhich various combinations of hydrogen atoms are replaced by deuteriumatoms, so that some, most or all of these hydrogen atoms have beenreplaced by deuterium atoms. Half-life determinations enable favourableand accurate determination of the extent of the extent to which theimprovement in resistance to oxidative metabolism has improved. In thisway, it is determined that the half-life of the parent compound can beextended by up to 100% as the result of deuterium-hydrogen exchange ofthis type.

Deuterium-hydrogen exchange in a compound of the formula Ia or Ib canalso be used to achieve a favourable modification of the metabolitespectrum of the starting compound in order to diminish or eliminateundesired toxic metabolites. For example, if a toxic metabolite arisesthrough oxidative carbon-hydrogen (C—H) bond cleavage, it can reasonablybe assumed that the deuterated analogue will greatly diminish oreliminate production of the unwanted metabolite, even if the particularoxidation is not a rate-determining step. Further information on thestate of the art with respect to deuterium-hydrogen exchange may befound, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990,Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res.14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, andJarman et al. Carcinogenesis 16(4), 683-688, 1993.

The invention furthermore relates to medicaments comprising at least onecompound of the formula Ia or Ib and/or pharmaceutically acceptablesalts, tautomers and stereoisomers thereof, including mixtures thereofin all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient.

Furthermore, pharmaceutical formulations of this type can be preparedusing a process which is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, been-capsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula Ia or Ib and pharmaceutically acceptablesalts, tautomers and stereoisomers thereof can also be administered inthe form of liposome delivery systems, such as, for example, smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from various phospholipids, such as,for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula Ia or Ib and the pharmaceuticallyacceptable salts, tautomers and physiologically functional derivativesthereof can also be delivered using monoclonal antibodies as individualcarriers to which the compound molecules are coupled. The compounds canalso be coupled to soluble polymers as targeted medicament carriers.Such polymers may encompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, poly-acetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Ia or Ibdepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention is generally in the range from 0.1 to 100 mg/kg of body weightof the recipient (mammal) per day and particularly typically in therange from 1 to 10 mg/kg of body weight per day. Thus, the actual amountper day for an adult mammal weighing 70 kg is usually between 70 and 700mg, where this amount can be administered as a single dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound according to the invention per se. It can beassumed that similar doses are suitable for the treatment of otherconditions mentioned above.

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

The invention furthermore relates to medicaments comprising at least onecompound of the formula Ia or Ib and/or pharmaceutically acceptablesalts, tauotmers and stereoisomers thereof, including mixtures thereofin all ratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula Ia or Ib and/or    pharmaceutically acceptable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula Ia or Ib and/or pharmaceutically acceptable salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

“Treating” as used herein, means an alleviation, in whole or in part, ofsymptoms associated with a disorder or disease, or slowing, or haltingof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder in a subject at risk fordeveloping the disease or disorder.

The term “effective amount” in connection with a compound of formula Iaor Ib can mean an amount capable of alleviating, in whole or in part,symptoms associated with a disorder or disease, or slowing or haltingfurther progression or worsening of those symptoms, or preventing orproviding prophylaxis for the disease or disorder in a subject having orat risk for developing a disease disclosed herein, such as inflammatoryconditions, immunological conditions, cancer or metabolic conditions.

In one embodiment an effective amount of a compound of formula Ia or Ibis an amount that inhibits PDHK in a cell, such as, for example, invitro or in vivo. In some embodiments, the effective amount of thecompound of formula Ia or Ib inhibits PDHK in a cell by 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the activity of PDHK inan untreated cell. The effective amount of the compound of formula Ia orIb, for example in a pharmaceutical composition, may be at a level thatwill exercise the desired effect; for example, about 0.005 mg/kg of asubject's body weight to about 10 mg/kg of a subject's body weight inunit dosage for both oral and parenteral administration.

Use

The present invention specifically relates to compounds of the formulaIa or Ib and pharmaceutically acceptable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios, for theuse for the treatment of cancer, diabetes and heart ischemia.

Moreover, the present invention relates to compounds of the formula Iaor Ib and pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for thetreatment of insulin resistance syndrome, metabolic syndrome,hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure,cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrialdisease, mitochondrial encephalomyopathy.

The present invention specifically relates to methods for treating orpreventing cancer, diabetes and heart ischemia, comprising administeringto a subject in need thereof an effective amount of a compound offormula Ia or Ib or a pharmaceutically acceptable salt, tautomer,stereoisomer or solvate thereof.

Also encompassed is the use of the compounds of the formula Ia or Iband/or pharmaceutically acceptable salts, tautomers and stereoisomersthereof for the preparation of a medicament for the treatment orprevention of a PDHK-induced disease or a PDHK-induced condition in amammal, in which to this method a therapeutically effective amount of acompound according to the invention is administered to a sick mammal inneed of such treatment. The therapeutic amount varies according to thespecific disease and can be determined by the person skilled in the artwithout undue effort.

The expression “PDHK-induced diseases or conditions” refers topathological conditions that depend on the activity of PDHK. Diseasesassociated with PDHK activity include cancer, diabetes and heartischemia.

The present invention specifically relates to compounds of the formulaIa or Ib and pharmaceutically acceptable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios, for theuse for the treatment of diseases in which the inhibition, regulationand/or modulation inhibition of PDHK plays a role.

The present invention specifically relates to compounds of the formulaIa or Ib and pharmaceutically acceptable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios, for theuse for the inhibition of PDHK.

Representative cancers that compounds of formula Ia or Ib are useful fortreating or preventing include, but are not limited to, cancer of thehead, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx,chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder,uterine, cervix, breast, ovaries, testicles or other reproductiveorgans, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas,brain, central nervous system, solid tumors and blood-borne tumors.

Moreover, representative cancers that compounds of formula Ia or Ib areuseful for treating or preventing include cancer of brain (gliomas),glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease,Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm'stumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma,colon, head and neck, kidney, lung, liver, melanoma, ovarian,pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of boneand thyroid.

Preferably, the present invention relates to a method wherein thedisease is a cancer.

Particularly preferable, the present invention relates to a methodwherein the disease is a cancer, wherein administration is simultaneous,sequential or in alternation with administration of at least one otheractive drug agent.

The disclosed compounds of the formula Ia or Ib can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaIa or Ib, conventional surgery or radiotherapy or medicinal therapy.Such medicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating Agents

such as altretamine, bendamustine, busulfan, carmustine, chlorambucil,chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan,tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine,ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine,carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide,pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;

Platinum Compounds

such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate,oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA Altering Agents

such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine,trabectedin, clofarabine;

amsacrine, brostallicin, pixantrone, laromustine^(1,3);

Topoisomerase Inhibitors

such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide,topotecan;

amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule Modifiers

such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel,vinblastine, vincristine, vinorelbine, vindesine, vinflunine;

fosbretabulin, tesetaxel;

Antimetabolites

such as asparaginase³, azacitidine, calcium levofolinate, capecitabine,cladribine, cytarabine, enocitabine, floxuridine, fludarabine,fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine,pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur;

doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur^(2,3),trimetrexate;

Anticancer Antibiotics

such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin,levamisole, miltefosine, mitomycin C, romidepsin, streptozocin,valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin;

aclarubicin, peplomycin, pirarubicin;

Hormones/Antagonists

such as abarelix, abiraterone, bicalutamide, buserelin, calusterone,chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolonefluoxymesterone, flutamide, fulvestrant, goserelin, histrelin,leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide,octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa,toremifene, trilostane, triptorelin, diethylstilbestrol;

acolbifene, danazol, deslorelin, epitiostanol, orteronel,enzalutamide^(1,3);

Aromatase Inhibitors

such as aminoglutethimide, anastrozole, exemestane, fadrozole,letrozole, testolactone;

formestane;

Small Molecule Kinase Inhibitors

such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib,nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib,vandetanib, vemurafenib, bosutinib, gefitinib, axitinib;

afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib,enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib,midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib,radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, trametinib,pimasertib, brivanib alaninate, cediranib, apatinib⁴, cabozantinibS-malate^(1,3), ibrutinib^(1,3), icotinib⁴, buparlisib², cipatinib⁴,cobimetinib^(1,3), idelalisib^(1,3), fedratinib¹, XL-647⁴;

Photosensitizers

such as methoxsalen³;

porfimer sodium, talaporfin, temoporfin;

Antibodies

such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab,denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab,trastuzumab, bevacizumab, pertuzumab^(2,3);

catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab,necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab,ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab,zanolimumab, matuzumab, dalotuzumab^(1,2,3), onartuzumab^(1,3),racotumomab¹, tabalumab^(1,3), EMD-525797⁴, nivolumab^(1,3);

Cytokines

such as aldesleukin, interferon alfa², interferon alfa2a³, interferonalfa2b^(2,3); celmoleukin, tasonermin, teceleukin, oprelvekin^(1,3),recombinant interferon beta-1a⁴;

Drug Conjugates

such as denileukin diftitox, ibritumomab tiuxetan, iobenguane I123,prednimustine, trastuzumab emtansine, estramustine, gemtuzumab,ozogamicin, aflibercept;

cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomabestafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab^(1,3),vintafolide^(1,3);

Vaccines

such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴, rindopepimut³,troVax⁴, MGN-1601⁴, MGN-1703⁴;

Miscellaneous

alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid,imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronicacid, pegaspargase, pentostatin, sipuleucel³, sizofiran, tamibarotene,temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid,vorinostat;

celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil,iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin,plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod,telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen,ubenimex, valspodar, gendicine⁴, picibanil⁴, reolysin⁴, retaspimycinhydrochloride^(1,3), trebananib^(2,3), virulizin⁴, carfilzomib^(1,3),endostatin⁴, immucothel⁴, belinostat³, MGN-1703⁴; ¹ Prop. INN (ProposedInternational Nonproprietary Name)² Rec. INN (Recommended InternationalNonproprietary Names)³ USAN (United States Adopted Name)⁴ no INN.

The following abbreviations refer respectively to the definitions below:

aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz(Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM(millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), L(microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane),DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF(dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d₆ (deuterateddimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MeOH (methanol), MgSO₄ (magnesium sulfate), MS (massspectrometry), MTBE (Methyl tert-butyl ether), NaHCO₃ (sodiumbicarbonate), NaBH₄ (sodium borohydride), NMM (N-methyl morpholine), NMR(Nuclear Magnetic Resonance), PyBOP(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SPE(solid phase extraction), TBTU(2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet).

Description of the In Vitro Assays

ABBREVIATIONS

GST=Glutathione-S-transferase

FRET=Fluorescence resonance energy transfer

HTRF®=(homogenous time resolved fluorescence)

HEPES=4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid buffer

DTT=Dithiothreitol

BSA=bovine serum albumin

CHAPS=3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate

Biochemical Activity Testing of PDHK2: PDC Inactivation Assay

The biochemical activity assay for PDHK2 is based on the inactivation ofPDC through phosphorylation by PDHK2. The assay is run in two steps: theenzymatic PDHK2 reaction in which isolated PDC is phosphorylated byPDHK2 with ATP as co-substrate and the PDC activity assay in whichpyruvate and NAD are converted to acetyl-CoA and NADH. The PDC activitycorrelates to the increase in NADH and thereby is detectable directlyvia the increasing fluorescence signal (Exc 340 nm, Em 450 nm).Inhibition of PDHK2 results in a lower phosphorylation status andthereby a less decrease in activity of PDC and a stronger increase inNADH fluorescence signal.

The PDC inactivation assay is performed in Greiner 384-well microtiterplates and is used for high throughput screen. 4 μl of PDHK2 (human,rec, Carna Bioscience, 10 ng/μl-137 nM final concentration) and PDC(isolated from porcine heart, Sigma-Aldrich, 20 mU/ml finalconcentration) are incubated in the absence or presence of the testcompound (10 dilution concentrations) for 30 min at room temperature inkinase buffer (15 mM potassium phosphate buffer, pH 7.0, 60 mM KCl, 1.5mM DTT, 2.5 mM MgCl₂, 0.0125% (w/v) BSA, 0.125% Pluronic F-68). Thekinase reaction is started by the addition of 4 μl ATP substratesolution (fc 5 μM in kinase buffer). After 30 min incubation at 37° C.40 μl of PDC reaction solution (100 mM Tris/HCl, pH 7.8, 0.5 mM EDTA, 1mM MgCl₂, 50 mM NaF, 0.25 mM Coenzyme A, 5 mM pyruvate, 1 mM NAD, 5 mMDTT, 1 mM thiamine pyrophosphate) is added. The first fluorescencemeasurement is performed on a Perkin Elmer Envision (Exc 340 nm, Em 450nm). The reaction is incubated for 45 min at room temperature.Afterwards a second fluorescence measurement is performed and the PDCactivity is calculated by the difference between both measurements. Asfull value for the PDHK2 assay the inhibitor-free PDHK2 reaction isused. The pharmacological zero value used is DCA (Sigma-Aldrich) in afinal concentration of 3 mM. The inhibitory values (1050) weredetermined using either the program Symyx Assay Explorer® or Condosseo®from GeneData.

Isothermal Titration Calorimetry

ITC measurements were performed with a VP-ITC micro calorimeter(Microcal, LLC/GE Healthcare Bio-Sciences Aft Uppsala, Sweden). Ingeneral titrations were performed by titrating the protein (50 μM) tothe test compound (5 μM) in 12 μl injections. All binding experimentswere carried out at 30° C. In general the test compounds were dilutedform DMSO stock solutions into the measurement buffer with a maximumfinal concentration of 1% DMSO. The measurement buffer was 20 mM HEPES,135 mM KCl, 1 mM TCEP, 2 mM MgCl₂, 15 mM NaH₂PO₄, pH 7.5. The humanPDHK2 (12-407) was produced in E. coli as his-tagged protein andpurified by affinity chromatography. The tag was removed by sidespecific proteolysis. Before titration the protein buffer was changed tothe measurement buffer containing the same DMSO concentration as thetest compound dilution. ITC data analysis was performed using Origin 7calorimetry software from the same supplier. For most measurements abinding model of one binding site was assumed. According to the appliedmathematical model it is possible to calculate the binding constant(K_(A)), the observed binding enthalpy (ΔH^(obs)) as well as thestoichiometry (N) of the formed complex.

Preceding analysis the raw data was corrected for the heats of dilutionby extrapolating from the saturation value from the end of titration. Inorder to allow for direct comparison between the respective experimentalseries and protein preparations the protein concentration was correctedby referencing titrations to a well behaved standard inhibitor. Theapparent stoichiometry values defined the fraction of binding competentprotein and compensated for relative errors in protein concentrationmeasurements. This corrected protein concentration was used to set upITC experiment series with test compounds. Any deviations from ideal 1:1stoichiometry observed here were attributed to errors in compoundconcentration. This nominal compound concentration was corrected as wellto achieve 1:1 stoichiometry in the fit.

Cellular Assay for Determination of Compound Activities

Compound activities were determined in a cellular immunofluorescenceassay. Human HEK293T cells were seeded into black 384-well plates withclear bottom and grown overnight.

Next day, test compounds were added to the wells and the platesincubated for 5 hours. Following this, cells were fixed withformaldehyde, permeabilised and blocked. The primary antibody,Anti-PDH-E1alpha (pSer300), AP1064 (Merck Millipore) was added andincubated overnight in the plate wells. Next, cells were washed and thesecondary antibody, Alexa Fluor 488, goat anti-rabbit ab (A-11008,Invitrogen) was added together with Hoechst 33258 (H3569, Invitrogen)and incubated for 1 hour in the plate wells. Finally, cells were washedand the plates were measured on the laser scanning cytometer acumen hci(TTpLabtech).

The raw data were normalized against a pharmacological inhibitor controland dose response curves were generated by plotting the percent effectvalues using the software package Genedata screener (Genedata).

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation.

LC/MS:

HPLC-Method:

Gradient: 3.3 min; Flow: 2.4 ml/min from 0 min 4% B, 2.8 min 100% B, 3.3min 100% B

A: Water+HCOOH (0.05% Vol.); B: Acetonitril+HCOOH (0.04% Vol.)

Column: Chromolith SpeedROD RP 18e 50-4.6

Wave Length: 220 nm

Agilent Apparatus

¹H NMR was recorded on Bruker DPX-300, DRX-400, AVII-400 or BRUKER 500MHz spectrometer, using residual signal of deuterated solvent asinternal reference. Chemical shifts (δ) are reported in ppm relative tothe residual solvent signal (δ=2.49 ppm for ¹H NMR in DMSO-d₆). ¹H NMRdata are reported as follows: chemical shift (multiplicity, couplingconstants, and number of hydrogens). Multiplicity is abbreviated asfollows: s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

EXAMPLES

General reaction scheme for manufacturing compounds of formula Ia inwhich X═N and Y═CH

Example 1(2R)-1-[1-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A1”)

1.11-(4-Chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicAcid tert-butyl ester

3-[1-Dimethylamino-meth-(E)-ylidene]-4-oxo-piperidine-1-carboxylic acidtert-butyl ester (200 mg; 0.786 mmol) and 4-chlorophenylhydrazinehydrochloride (155 mg; 0.865 mmol) were suspended in methanol (4 mL) andwater (1 mL). Glacial acetic acid (0.23 mL; 3.932 mmol) was added whilestirring and a few minutes later an orange solution was formed. Themixture was stirred for 1 h at room temperature, diluted with ethylacetate, washed with water, saturated NaHCO₃ solution and brine, driedwith Na₂SO₄, filtered and evaporated to dryness. The oily residue waspurified by flash chromatography (Companion RF; 40 g Si50 silica gelcolumn). Yield: 145.5 mg brown oil; LC/MS, Rt: 2.61 min; (M+H) 334.1

1.2 1-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinedihydrochloride

Compound 1.1 (145.5 mg; 0.436 mmol) was dissolved in dry 1,4-dioxane (3mL) and hydrogen chloride (4 M solution in dioxane; 4 mL) was added atroom temperature. After a few minutes a light brown solid precipitated.The reaction mixture was stirred for 2 h at room temperature, dilutedwith diethylether (7 mL) and stirred for 5 min. The precipitate wasfiltered by suction, washed with diethylether and dried for 2 h at roomtemperature. Yield: 155 mg yellow solid; LC/MS, Rt: 1.16 min; (M+H)234.1

1.3(2R)-1-[1-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

Compound 1.2 (155 mg; 0.505 mmol),(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (159 mg; 1.006mmol) and[dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium;hexafluoro phosphate (383 mg; 1.007 mmol) were dissolved in DMF (2.5mL). N-Ethyldiisopropylamine (0.857 mL; 5.037 mmol) was added and theyellow solution was stirred overnight at room temperature. The reactionmixture was diluted with water (40 mL) and extracted ethyl acetate. Thecombined organic layers were washed with saturated NaHCO₃ solution, andbrine, dried with Na₂SO₄, filtered and evaporated to dryness. Theresidue was purified by flash chromatography (Companion RF, 24 g Si50silica gel column) and subsequently by preparative HPLC (Agilent 1260;column: Waters SunFire C18, 5 μm, 30×150 mm). The collected fractionswith product were combined and evaporated to an aqueous residue. Thisaqueous residue was rendered basic with saturated NaHCO₃ solution andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried with Na₂SO₄, filtered, evaporated to dryness, and theresidue was lyophilized.

Yield: 114 mg (60%) pale-yellow powder; LC/MS, Rt: 2.19 min; (M+H)374.1;

¹H NMR (500 MHz, DMSO-d₆) δ 7.66-7.51 (m, 5H), 7.19 (s, 1H), 5.14-4.84(m, 1H), 4.65-4.47 (m, 1H), 4.23-3.96 (m, 1H), 3.90-3.64 (m, 1H),3.04-2.80 (m, 2H), 1.66-1.46 (m, 3H).

Example 2(2R)-1-[2-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A2”)

“A2”, which is the isomeric cyclisation product of step 1.1, wasisolated in step 1.3 by preparative HPLC (Agilent 1260; column: WatersSunFire C18, 5 μm, 30×150 mm). Yield: 7 mg (4%) colorless powder; LC/MS,Rt: 2.26 min; (M+H) 374.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (s, 1H),7.82-7.76 (m, 2H), 7.55-7.50 (m, 2H), 7.21 (s, 1H), 5.16-4.94 (m, 1H),4.69-4.50 (m, 1H), 4.28-4.02 (m, 1H), 3.94-3.68 (m, 1H), 2.93-2.68 (m,2H), 1.66-1.45 (m, 3H).

Example 3(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(1-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one(“A3”)

Preparation as described for example 1 (steps 1.1-1.3). Yield: 142 mg(62%) colorless solid; LC/MS, Rt: 1.97 min; (M+H) 340.1; ¹H NMR (400MHz, DMSO-d₆) δ 7.58-7.52 (m, 3H), 7.52-7.45 (m, 2H), 7.38-7.31 (m, 1H),6.87 (s, 1H), 4.73 (s, 2H), 4.09-3.90 (m, 2H), 2.91 (t, J=5.8 Hz, 2H),1.58 (s, 3H).

Example 4(R)-3,3,3-Trifluoro-1-[1-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A4”)

Preparation as described for example 1 (steps 1.1-1.3). Yield: 102 mg(77%) colorless solid; LC/MS, Rt: 2.02 min; (M+H) 358.2; ¹H NMR (400MHz, DMSO-d₆) δ 7.63-7.54 (m, 3H), 7.35-7.27 (m, 2H), 6.90 (s, 1H),4.81-4.67 (m, 2H), 4.09-3.93 (m, 2H), 2.90 (t, J=5.8 Hz, 2H), 1.60 (s,3H).

Example 5(R)-1-[1-(2,4-Difluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A5”)

Preparation as described for example 1 (steps 1.1-1.3). Yield: 160 mg(77%) pale-yellow solid; LC/MS, Rt: 1.99 min; (M+H) 376.1; ¹H NMR (400MHz, DMSO-d₆) δ 7.68-7.50 (m, 3H), 7.26 (t, J=7.9 Hz, 1H), 7.23-7.10 (m,1H), 5.18-3.62 (m, 4H), 2.81-2.54 (m, 2H), 1.56 (s, 3H).

Example 6(R)-1-[2-(2,4-Difluoro-phenyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A6”)

The isomeric cyclisation product of step 5.1 was isolated by flashchromatography (Companion RF; 24 g Si50 silica gel column) and convertedto example 6 as described for example 1 (steps 1.2-1.3). Yield: 51 mg(79%) colorless solid; LC/MS, Rt: 2.09 min; (M+H) 376.1; ¹H NMR (400MHz, DMSO-d₆, 80° C.) δ 7.95 (d, J=2.4 Hz, 1H), 7.81-7.74 (m, 1H),7.46-7.39 (m, 1H), 7.23-7.16 (m, 1H), 6.95 (s, 1H), 4.88-4.73 (m, 2H),4.15-3.95 (m, 2H), 2.82 (t, J=5.9 Hz, 2H), 1.59 (s, 3H).

Example 7(R)-1-(1-tert-Butyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A7”)

Preparation as described for example 1 (steps 1.1-1.3). Yield: 131 mg(57%) yellow solid; LC/MS, Rt: 1.85 min; (M+H) 320.2; ¹H NMR (500 MHz,DMSO-d₆) δ 7.23 (s, 1H), 7.15 (s, 1H), 5.07-3.61 (m, 4H), 3.07-2.80 (m,2H), 1.52 (s, 12H).

Example 8(R)-1-(2-tert-Butyl-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A8”)

The isomeric cyclisation product of step 7.1 was isolated by preparativeHPLC (Agilent 1260; column: Waters SunFire C18, 5 μm, 30×150 mm) andconverted to example 8 as described for example 1 (steps 1.2-1.3).Yield: 16 mg (26%) colorless solid; LC/MS, Rt: 1.85 min; (M+H) 320.1.

General reaction scheme for manufacturing compounds of formula Ia inwhich X═N, Y═CH and R² denotes CH₃

Example 9(2R)-1-[1-(4-chlorophenyl)-7-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A9”); Mixture of diastereomers

9.13-[1-Dimethylamino-meth-(E)-ylidene]-5-methyl-4-oxo-piperidine-1-carboxylicAcid tert-butyl ester

N-Boc-3-methyl-4-piperidone (1.00 g; 4.689 mmol) was dissolved intert-butoxy bis(dimethylamino)methane (1.14 g; 6.564 mmol). The reactionvial was sealed with a septum and stirred for 30 min at 100° C. Thereaction mixture was cooled to room temperature, diluted with water (20mL) and extracted with ethyl acetate. The combined organic layers werewashed with brine, dried with Na₂SO₄, filtered by suction and evaporatedto dryness. The yellow oil (1.24 g) was used in the next step withoutfurther purification. Steps 9.2-9.4 were performed as described forexample 1 (steps 1.1-1.3).

Yield: 179 mg (74%) colorless solid; LC/MS, Rt: 2.22 min; (M+H) 388.1;¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ 7.62-7.52 (m, 5H), 6.91 (d, J=3.2Hz, 1H), 5.11-4.76 (m, 1H), 4.69 (dd, J=15.8, 8.9 Hz, 1H), 3.95 (dd,J=13.1, 5.3 Hz, 1H), 3.92-3.76 (m, 1H), 3.42 (h, J=6.2 Hz, 1H),1.63-1.57 (m, 3H), 0.89 (dd, J=6.8 Hz, 2.5 Hz, 3H).

Example 10(R)-1-[(R)-1-(4-Chloro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A10”)

Example 11(R)-1-[(S)-1-(4-Chloro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A11”)

The preparative separation of the diastereomers of example 9 wasperformed by SFC (column: ChiralCel OJ-H; eluent: CO₂:methanol—92:8).The combined fractions were evaporated to dryness. The oily residue wasdissolved in acetonitrile, diluted with water and lyophilized.

“A10”: 66 mg colorless solid; LC/MS, Rt: 2.22 min; (M+H) 388.1; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.68-7.47 (m, 4H), 6.94 (s, 1H), 5.08-4.55(m, 2H), 4.08-3.66 (m, 2H), 3.51-3.32 (m, 1H), 1.60 (s, 3H), 0.88 (d,J=6.8 Hz, 3H).

“A11”: 68 mg yellow solid; LC/MS, Rt: 2.23 min; (M+H) 388.1; ¹H NMR (400MHz, DMSO-d₆, 80° C.) δ 7.65-7.48 (m, 4H), 6.94 (s, 1H), 5.20-4.59 (m,2H), 4.08-3.66 (m, 2H), 3.52-3.30 (m, 1H), 1.58 (s, 3H), 0.87 (d, J=6.8Hz, 3H).

Example 12(2R)-3,3,3-trifluoro-1-[1-(4-fluorophenyl)-7-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A12”); Mixture of diastereomers

Preparation as described for “A9” (steps 9.1-9.4). Yield: 185 mg (66%)colorless solid; LC/MS, Rt: 2.07 min; (M+H) 372.2; ¹H NMR (400 MHz,DMSO-d₆, 80° C.) δ 7.60-7.49 (m, 3H), 7.37-7.27 (m, 2H), 6.96 (s, 1H),5.17-4.77 (m, 1H), 4.68 (dd, J=15.7, 7.5 Hz, 1H), 3.98-3.75 (m, 2H),3.36 (h, J=6.2 Hz, 1H), 1.58 (d, J=5.3 Hz, 3H), 0.84 (dd, J=6.8, 2.3 Hz,3H).

Example 13(2R)-3,3,3-trifluoro-1-[2-(4-fluorophenyl)-7-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A13”); Mixture of diastereomers

The isomeric cyclisation product of step 12.1 was isolated by flashchromatography (Companion RF; 24 g Si50 silica gel column) and convertedto example 13 as described for example 9 (steps 9.3-9.4). Yield: 29 mg(75%) colorless powder; LC/MS, Rt: 2.20/2.22 min; (M+H) 372.1; ¹H NMR(400 MHz, DMSO-d₆) δ 8.29-8.24 (m, 1H), 7.83-7.75 (m, 2H), 7.37-7.28 (m,2H), 7.27-7.14 (m, 1H), 5.34-4.97 (m, 1H), 4.95-4.50 (m, 1H), 4.25-3.91(m, 1H), 3.39-3.20 (m, 1H), 3.19-2.89 (m, 1H), 1.68-1.45 (m, 3H), 1.25(d, J=5.8 Hz, 3H).

Example 14(R)-3,3,3-Trifluoro-1-[(R)-1-(4-fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A14”)

Example 15(R)-3,3,3-Trifluoro-1-[(S)-1-(4-fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A15”)

The preparative separation of the diastereomers of example 12 wasperformed by SFC (column: ChiralCel OJ-H; eluent: CO₂:methanol—95:5).The combined fractions were evaporated to dryness. The oily residue wasdissolved in acetonitrile, diluted with water and lyophilized.

“A14”: 66 mg colorless solid; LC/MS, Rt: 2.07 min; (M+H) 372.1; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.64-7.52 (m, 2H), 7.51 (s, 1H), 7.38-7.22(m, 2H), 6.92 (s, 1H), 5.18-4.50 (m, 2H), 4.00-3.58 (m, 2H), 3.50-3.20(m, 1H), 1.58 (s, 3H), 0.84 (d, J=6.8 Hz, 3H).

“A15”: 65 mg colorless solid; LC/MS, Rt: 2.08 min; (M+H) 372.1; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.64-7.53 (m, 2H), 7.51 (s, 1H), 7.39-7.23(m, 2H), 6.91 (s, 1H), 5.16-4.56 (m, 2H), 4.19-3.58 (m, 2H), 3.44-3.27(m, 1H), 1.57 (s, 3H), 0.83 (d, J=6.8 Hz, 3H).

Alternative method for the preparation of “A14” and “A15”: Preparativeseparation of the enantiomers of the Boc-protected cyclization products(step 12.1) was accomplished by SFC (column: ChiralCel OJ-H; eluent:CO₂:2-propanol—95:5). Both enantiomers were converted to “A14” and “A15”respectively as described for “A9” (steps 9.3-9.4).

Example 16(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(7-methyl-1-phenyl-1,4,6,7-tetra-hydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one(“A16”); Mixture of diastereomers

Preparation as described for “A9” (steps 9.1-9.4). Yield: 176 mg (78%)colorless solid; LC/MS, Rt: 2.02 min; (M+H) 354.2; ¹H NMR (400 MHz,DMSO-d₆, 80° C.) δ 7.56-7.48 (m, 5H), 7.46-7.38 (m, 1H), 6.94 (s, 1H),5.16-4.77 (m, 1H), 4.70 (dd, J=15.6, 6.6 Hz, 1H), 4.02-3.73 (m, 2H),3.41 (h, J=6.3 Hz, 1H), 1.59 (d, J=5.0 Hz, 3H), 0.85 (dd, J=6.8, 2.7 Hz,3H).

Example 17(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(7-methyl-2-phenyl-2,4,6,7-tetra-hydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one(“A17”); Mixture of diastereomers

The isomeric cyclisation product of step 16.1 was isolated by flashchromatography (Companion RF; 24 g Si50 silica gel column) and convertedto example 17 as described for “A9” (steps 9.3-9.4). Yield: 41 mg (71%)pale-yellow solid; LC/MS, Rt: 2.16/2.18 min; (M+H) 354.2; ¹H NMR (400MHz, DMSO-d₆) δ 8.33-8.25 (m, 1H), 7.79-7.73 (m, 2H), 7.52-7.44 (m, 2H),7.31-7.25 (m, 1H), 7.25-7.12 (m, 1H), 5.36-4.99 (m, 1H), 4.97-4.53 (m,1H), 4.27-3.88 (m, 1H), 3.41-2.92 (m, 2H), 1.69-1.44 (m, 3H), 1.31-1.19(m, 3H).

Example 18(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-((R)-7-methyl-1-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one(“A18”)

Example 19(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-((S)-7-methyl-1-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one(“A19”)

The preparative separation of the diastereomers of “A16” was performedby SFC (column: ChiralCel OJ-H; eluent: CO₂:methanol—95:5). The combinedfractions were evaporated to dryness. The oily residue was dissolved inacetonitrile, diluted with water and lyophilized.

“A18”: 54 mg colorless solid; LC/MS, Rt: 2.02 min; (M+H) 354.2; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.57-7.45 (m, 5H), 7.45-7.33 (m, 1H), 6.92(s, 1H), 5.32-4.45 (m, 2H), 4.14-3.53 (m, 2H), 3.53-3.25 (m, 1H), 1.58(d, 3H), 0.84 (d, J=6.8 Hz, 3H).

“A19”: 63 mg colorless solid; LC/MS, Rt: 2.03 min; (M+H) 354.1; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.57-7.46 (m, 5H), 7.45-7.34 (m, 1H), 6.91(s, 1H), 5.23-4.51 (m, 2H), 4.10-3.59 (m, 2H), 3.50-3.31 (m, 1H), 1.57(s, 3H), 0.83 (d, J=6.8 Hz, 3H).

Example 20(R)-1-[(R)-1-(2,4-Difluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A20”)

Example 21(R)-1-[(S)-1-(2,4-Difluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A21”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by SFC (column: ChiralPakAS-H; eluent: CO₂:2-propanol—97:3). The combined fractions wereevaporated to dryness. The oily residue was dissolved in acetonitrile,diluted with water and lyophilized.

“A20”: 35 mg colorless solid; LC/MS, Rt: 2.09 min; (M+H) 390.1; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.68-7.53 (m, 2H), 7.53-7.40 (m, 1H),7.33-7.14 (m, 1H), 6.97 (s, 1H), 5.32-4.36 (m, 2H), 4.22-3.47 (m, 2H),3.25-2.87 (m, 1H), 1.60 (s, 3H), 0.82 (d, J=6.9 Hz, 3H).

“A21”: 35 mg colorless solid; LC/MS, Rt: 2.10 min; (M+H) 390.1; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.67-7.54 (m, 2H), 7.53-7.40 (m, 1H),7.27-7.18 (m, 1H), 6.96 (s, 1H), 5.08-4.49 (m, 2H), 4.21-3.44 (m, 2H),3.19-2.96 (m, 1H), 1.58 (s, 3H), 0.81 (d, J=6.8 Hz, 3H).

Example 22(R)-1-((R)-1-tert-Butyl-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A22”)

Example 23(R)-1-((S)-1-tert-Butyl-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A23”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by SFC (column: ChiralPakAD-H; eluent: CO₂:2-methanol—92:8). The combined fractions wereevaporated to dryness. The oily residue was dissolved in acetonitrile,diluted with water and lyophilized.

“A22”: 52 mg colorless solid; LC/MS, Rt: 1.99 min; (M+H) 334.2; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.20 (s, 1H), 6.87 (s, 1H), 5.24 (s, 1H),4.65 (s, 1H), 4.18 (d, J=15.5 Hz, 1H), 3.51-3.25 (m, 1H), 3.11-2.93 (m,1H), 1.59 (s, 3H), 1.56 (s, 9H), 1.19 (d, J=6.7 Hz, 3H).

“A23”: 42 mg colorless solid; LC/MS, Rt: 1.85 min; (M+H) 334.2; ¹H NMR(400 MHz, DMSO-d₆, 80° C.) δ 7.21 (s, 1H), 6.84 (s, 1H), 5.36-5.02 (m,1H), 4.60 (d, J=12.8 Hz, 1H), 4.21 (d, J=16.0 Hz, 1H), 3.40-3.32 (m,1H), 3.07-2.98 (m, 1H), 1.59-1.53 (m, 12H), 1.19 (d, J=6.7 Hz, 3H).

Example 24(R)-3,3,3-Trifluoro-1-[(R)-1-(2-fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A24”)

Example 25(R)-3,3,3-Trifluoro-1-[(S)-1-(2-fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A25”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by SFC (column: ChiralPakAS-H; eluent: CO₂:2-propanol—90:10). The combined fractions wereevaporated to dryness. The oily residue was dissolved in acetonitrile,diluted with water and lyophilized.

“A24”: 43 mg colorless solid; LC/MS, Rt: 2.02 min; (M+H) 372.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.60-7.30 (m, 5H), 6.91 (s, 1H), 4.99-4.65(m, 2H), 4.05-3.71 (m, 2H), 3.16-3.05 (m, 1H), 1.59 (s, 3H), 0.81 (d,J=6.8 Hz, 3H).

“A25”: 45 mg colorless solid; LC/MS, Rt: 2.03 min; (M+H) 372.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.61-7.32 (m, 5H), 6.90 (s, 1H), 4.95-4.66(m, 2H), 4.13-3.60 (m, 2H), 3.15-3.04 (m, 1H), 1.59 (d, J=1.2 Hz, 3H),0.80 (d, J=6.8 Hz, 3H).

Example 262-[(R)-7-Methyl-5-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-benzonitrile(“A26”)

Example 272-[(S)-7-Methyl-5-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-benzonitrile(“A27”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by SFC (column: ChiralPakAD-H; eluent: CO₂:methanol (containing 0.5% diethylamine)—85:15). Thecombined fractions were evaporated to dryness. The oily residue wasdissolved in acetonitrile, diluted with water and lyophilized.

“A26”: 23 mg yellow solid; LC/MS, Rt: 2.03 min; (M+H) 379.1; ¹H NMR (400MHz, DMSO-d₆, 90° C.) δ 8.65 (s, 1H), 8.24 (dt, J=8.3, 1.1 Hz, 1H), 7.85(dt, J=8.7, 0.9 Hz, 1H), 7.67-7.59 (m, 1H), 7.30 (ddd, J=7.9, 6.8, 0.9Hz, 1H), 7.04 (s, 1H), 4.83-4.63 (m, 2H), 3.96-3.85 (m, 1H), 3.71-3.56(m, 1H), 3.08-2.94 (m, 1H), 1.63 (d, J=1.2 Hz, 3H), 1.50 (d, J=6.9 Hz,3H).

“A27”: 32 mg yellow solid; LC/MS, Rt: 2.06 min; (M+H) 379.1; ¹H NMR (400MHz, DMSO-d₆, 90° C.) δ 8.64 (s, 1H), 8.24 (dd, J=8.3, 1.2 Hz, 1H), 7.85(dd, J=8.7, 1.0 Hz, 1H), 7.63 (ddd, J=8.4, 6.7, 1.2 Hz, 1H), 7.34-7.27(m, 1H), 7.08 (s, 1H), 4.86-4.67 (m, 2H), 3.96-3.87 (m, 1H), 3.65-3.50(m, 1H), 3.13-3.02 (m, 1H), 1.68 (d, J=1.2 Hz, 3H), 1.50 (d, J=6.9 Hz,3H).

Example 28(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-((R)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one(“A28”)

Example 29(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-((S)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one(“A29”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by preparative HPLC(Agilent 1260; column: Waters SunFire C18, 5 μm, 30×150 mm). Thecombined fractions were evaporated to an aqueous residue, which wasrendered basic with saturated NaHCO₃ solution and extracted with ethylacetate. The combined organic layers were washed with brine, dried withNa₂SO₄, filtered and evaporated to dryness. The oily residue wasdissolved in acetonitrile, diluted with water and lyophilized.

“A28”: 30 mg colorless solid; LC/MS, Rt: 1.42 min; (M+H) 278.1;

“A29”: 34 mg colorless solid; LC/MS, Rt: 1.46 min; (M+H) 278.1.

Example 30(R)-3,3,3-Trifluoro-2-hydroxy-1-[(R)-1-(6-methoxy-pyridin-3-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one(“A30”)

Example 31(R)-3,3,3-Trifluoro-2-hydroxy-1-[(S)-1-(6-methoxy-pyridin-3-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one(“A31”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by preparative HPLC(column: LuxAmylose-2; eluent: n-heptane:2-propanol—70:30). The combinedfractions were evaporated to dryness. The oily residue was dissolved inacetonitrile, diluted with water and lyophilized.

“A30”: 87 mg colorless solid; LC/MS, Rt: 1.93 min; (M+H) 385.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.32 (d, J=2.7 Hz, 1H), 7.85 (dd, J=8.8,2.7 Hz, 1H), 7.54 (s, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.89 (s, 1H),5.09-4.80 (m, 1H), 4.66 (d, J=15.7 Hz, 1H), 4.02-3.92 (m, 4H), 3.87-3.71(m, 1H), 3.38-3.28 (m, 1H), 1.60 (d, J=1.2 Hz, 3H), 0.88 (d, J=6.8 Hz,3H).

“A31”: 82 mg colorless solid; LC/MS, Rt: 1.93 min; (M+H) 385.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.32 (d, J=2.5 Hz, 1H), 7.85 (dd, J=8.8,2.8 Hz, 1H), 7.54 (s, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.89 (s, 1H),5.05-4.77 (m, 1H), 4.68 (d, J=15.7 Hz, 1H), 4.02-3.77 (m, 5H), 3.39-3.27(m, 1H), 1.59 (d, J=1.1 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H).

Example 32(R)-3,3,3-Trifluoro-1-[(R)-1-(3-fluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A32”)

Example 33(R)-3,3,3-Trifluoro-1-[(S)-1-(3-fluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A33”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by preparative HPLC(column: ChiralPak AD-H; eluent: n-heptane:2-propanol—85:15). Thecombined fractions were evaporated to dryness. The oily residue wasdissolved in acetonitrile, diluted with water and lyophilized.

“A32”: 66 mg colorless solid; LC/MS, Rt: 1.82 min; (M+H) 373.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.41 (dt, J=4.7, 1.2 Hz, 1H), 7.97 (ddd,J=10.0, 8.3, 1.5 Hz, 1H), 7.65-7.55 (m, 2H), 6.93 (s, 1H), 5.07-4.68 (m,2H), 3.97-3.77 (m, 2H), 3.44-3.34 (m, 1H), 1.60 (d, J=1.3 Hz, 4H), 0.89(d, J=6.8 Hz, 4H).

“A33”: 65 mg colorless solid; LC/MS, Rt: 1.83 min; (M+H) 373.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.41 (dt, J=4.6, 1.2 Hz, 1H), 7.98 (ddd,J=10.1, 8.3, 1.4 Hz, 1H), 7.66-7.56 (m, 2H), 6.92 (s, 1H), 5.00-4.73 (m,2H), 4.10-3.72 (m, 2H), 3.44-3.33 (m, 1H), 1.59 (d, J=1.1 Hz, 3H), 0.88(d, J=6.8 Hz, 3H).

Example 34(R)-1-[(R)-1-(3,5-Difluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A34”)

Example 35(R)-1-[(S)-1-(3,5-Difluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A35”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by SFC (column: ChiralPakAS-H; eluent: CO₂:2-propanol (containing 0.5% diethylamine)—90:10). Thecombined fractions were evaporated to dryness. The oily residue wasdissolved in acetonitrile, diluted with water and lyophilized.

“A34”: 35 mg colorless solid; LC/MS, Rt: 1.94 min; (M+H) 391.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C., TFA) δ 8.37 (d, J=2.4 Hz, 1H), 7.90 (dd,J=10.1, 7.9 Hz, 1H), 7.59 (s, 1H), 5.06-4.69 (m, 2H), 4.02-3.80 (m, 2H),3.44-3.31 (m, 1H), 1.63 (s, 3H), 0.91 (d, J=6.8 Hz, 3H).

“A35”: 33 mg colorless solid; LC/MS, Rt: 1.95 min; (M+H) 391.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.55-8.37 (m, 1H), 8.14 (ddd, J=9.8, 8.3,2.5 Hz, 1H), 7.61 (s, 1H), 6.90 (s, 1H), 5.03-4.56 (m, 2H), 4.08-3.61(m, 2H), 3.41-3.20 (m, 1H), 1.57 (s, 3H), 0.86 (d, J=6.8 Hz, 3H).

Example 36(R)-3,3,3-Trifluoro-1-[(R)-1-(5-fluoro-2-methoxy-pyrimidin-4-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A36”)

Example 37(R)-3,3,3-Trifluoro-1-[(S)-1-(5-fluoro-2-methoxy-pyrimidin-4-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A37”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by SFC (column: ChiralPakAD-H; eluent: CO₂:methanol (containing 0.5% diethylamine)—85:15). Thecombined fractions were evaporated to dryness. The oily residue wasdissolved in acetonitrile, diluted with water and lyophilized.

“A36”: 46 mg colorless solid; LC/MS, Rt: 1.99 min; (M+H) 404.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C., TFA) δ 8.62 (d, J=3.9 Hz, 1H), 8.39 (s, 1H),5.24 (d, J=16.4 Hz, 1H), 4.68-4.36 (m, 2H), 3.99 (s, 3H), 3.28 (dd,J=13.1, 9.0 Hz, 1H), 3.20-3.05 (m, 1H), 1.61 (d, J=1.2 Hz, 3H), 1.29 (d,J=6.9 Hz, 3H).

“A37”: 48 mg colorless solid; LC/MS, Rt: 1.96 min; (M+H) 404.1; ¹H NMR(400 MHz, DMSO-d₆) δ 8.76 (d, J=3.9 Hz, 1H), 8.50 (s, 1H), 7.33-7.06 (m,1H), 5.41-5.02 (m, 1H), 5.02-4.51 (m, 1H), 4.24-3.89 (m, 4H), 3.39-2.93(m, 2H), 1.72-1.38 (m, 3H), 1.24 (d, J=6.7 Hz, 3H).

Example 38(R)-3,3,3-Trifluoro-2-hydroxy-1-[(R)-1-(4-hydroxy-cyclohexyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one(“A38”)

Example 39(R)-3,3,3-Trifluoro-2-hydroxy-1-[(S)-1-(4-hydroxy-cyclohexyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one(“A39”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by SFC (column: ChiralCelOJ-H; eluent: CO₂:methanol—90:10). The combined fractions wereevaporated to dryness.

The oily residue was dissolved in acetonitrile, diluted with water andlyophilized.

“A38”: 6 mg colorless solid; LC/MS, Rt: 1.66 min; (M+H) 376.2; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.21 (s, 1H), 6.82 (s, 1H), 5.21-4.95 (m,1H), 4.39-4.25 (m, 2H), 4.15-4.05 (m, 1H), 3.98 (tt, J=10.7, 3.5 Hz,1H), 3.90-3.79 (m, 1H), 3.46-3.29 (m, 1H), 3.20-3.04 (m, 1H), 2.41-2.09(m, 2H), 1.90-1.68 (m, 2H), 1.66-1.42 (m, 7H), 1.14 (d, J=6.8 Hz, 3H).

“A39”: 7 mg colorless solid; LC/MS, Rt: 1.65 min; (M+H) 376.2; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.22 (s, 1H), 6.80 (s, 1H), 5.24-4.90 (m,1H), 4.42-4.18 (m, 2H), 4.08 (d, J=2.8 Hz, 1H), 3.99 (tt, J=10.9, 3.7Hz, 1H), 3.91-3.79 (m, 1H), 3.48-3.30 (m, 1H), 3.21-3.08 (m, 1H),2.41-2.11 (m, 2H), 1.88-1.73 (m, 2H), 1.68-1.44 (m, 7H), 1.14 (d, J=6.8Hz, 3H).

Example 40(R)-3,3,3-Trifluoro-1-[(R)-1-(5-fluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A40”)

Example 41(R)-3,3,3-Trifluoro-1-[(S)-1-(5-fluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A41”)

Preparation as described for “A9” (steps 9.1-9.4). The preparativeseparation of the diastereomers was performed by SFC (column: ChiralPakAS-H; eluent: CO₂:methanol—85:15). The combined fractions wereevaporated to dryness.

The oily residue was dissolved in acetonitrile, diluted with water andlyophilized.

“A40”: 44 mg colorless solid; LC/MS, Rt: 2.17 min; (M+H) 373.2; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.47-8.40 (m, 1H), 7.94-7.83 (m, 2H), 7.60(s, 1H), 6.91 (s, 1H), 5.40-5.02 (s, 1H), 4.49-4.33 (m, 2H), 3.84-3.74(m, 1H), 3.59-3.37 (m, 1H), 1.62 (d, J=1.1 Hz, 3H), 1.14 (d, J=6.7 Hz,3H).

“A41”: 35 mg colorless solid; LC/MS, Rt: 2.16 min; (M+H) 373.2; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.44 (d, J=2.8 Hz, 1H), 7.95-7.84 (m, 2H),7.61 (s, 1H), 6.88 (s, 1H), 5.30-5.00 (m, 1H), 4.48 (d, J=16.2 Hz, 1H),4.28 (dd, J=12.9, 3.8 Hz, 1H), 3.84-3.73 (m, 1H), 3.67-3.43 (m, 1H),1.59 (s, 3H), 1.13 (d, J=6.7 Hz, 3H).

Example 421-[(R)-1-(4-Fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A42”)

Preparation according to the alternative method described for thesynthesis of “A14” and “A15”. After separation of the enantiomericBoc-protected cyclization products (step 12.1) BOC-deprotection andacylation with 2-hydroxy-2-methyl-propionic acid was performed asdescribed for “A9” (steps 9.3-9.4).

“A42”: 30 mg colorless solid; LC/MS, Rt: 1.82 min; (M+H) 318.2; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.60-7.54 (m, 2H), 7.52 (s, 1H), 7.36-7.28(m, 2H), 5.18 (s, 1H), 4.85 (d, J=15.8 Hz, 1H), 4.70 (d, J=15.8 Hz, 1H),3.95-3.78 (m, 2H), 3.40-3.28 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 0.86(d, J=6.8 Hz, 3H).

General reaction scheme for manufacturing compounds of formula Ia inwhich X═CH, Y═N and R² denotes H

Example 43(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-propan-1-one(“A43”)

43.1 1,4,6,7-Tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic Acidtert-butyl ester

4,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine (500.0 mg; 4.060 mmol) wassuspended in dry THF (10.0 mL) and DIPEA (1.59 mL; 9.338 mmol) and4-(dimethylamino)pyridine (99.2 mg; 0.812 mmol) were added followed bythe addition of di-tert-butyl dicarbonate (1.95 g; 8.932 mmol). Thereaction mixture was diluted with methanol (2.0 mL) and stirred for 16 hat room temperature. The reaction mixture was diluted with ethylacetate, washed with 0.5 N HCl, saturated NaHCO₃ solution and brine,dried with Na₂SO₄, filtered by suction and evaporated to dryness. Theresidue was suspended in methanol (5.0 mL) and treated with 1 N sodiumhydroxide solution (0.32 mL; 8.323 mmol). The reaction mixture wasstirred for 20 min at room temperature and concentrated under vacuum toan aqueous residue. This residue was diluted with water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried with Na₂SO₄, filtered by suction and evaporated to dryness.

Yield: 682.5 mg (75%) yellow oil

43.2 1-Phenyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylicAcid tert-butyl ester

1,4,6,7-Tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butylester (219.0 mg; 0.981 mmol), benzeneboronic acid (239.2 mg; 1.962 mmol)and copper(II)acetate (89.1 mg; 0.490 mmol) were suspended under argonin dry dichloromethane (4.0 mL). Dry pyridine (158 μl; 1.962 mmol) wasadded and the dark blue reaction mixture was stirred for 43 h at roomtemperature. Further benzeneboronic acid (239.2 mg; 1.962 mmol),copper(II)acetate (89.1 mg; 0.490 mmol) and dry pyridine (158 μl; 1.962mmol) was added under argon and the mixture was stirred for 21 h at roomtemperature. The reaction mixture was diluted with dichloromethane,washed with 15% ammonia solution water and brine, dried with Na₂SO₄,filtered by suction and evaporated to dryness. The oily residue waspurified by chromatography (Companion RF; 24 g Si50 silica gel column)and the isomers were separated by preparative HPLC (Agilent1260; column:Waters SunFire C18 5 μm 30×150 mm). The combined fractions wereevaporated to an aqueous residue, rendered basic with saturated NaHCO₃solution and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried with Na₂SO₄, filtered and evaporated todryness. Yield: 81 mg (28%) colorless oil; LC/MS, Rt: 1.65 min; (M+H)300.2.

Steps 43.3 (BOC-deprotection) and 43.4 (acylation) were performed asdescribed for example 9 (steps 9.3-9.4). Yield: 80.5 mg (78%) colorlesssolid; LC/MS, Rt: 1.38 min; (M+H) 340.1; ¹H NMR (400 MHz, DMSO-d₆, 90°C.) δ 7.80 (s, 1H), 7.59-7.50 (m, 2H), 7.48-7.41 (m, 3H), 6.89 (s, 1H),4.83-4.62 (m, 2H), 4.14-3.93 (m, 2H), 2.73 (t, J=5.8 Hz, 2H), 1.60 (s,3H).

Example 44(R)-3,3,3-Trifluoro-1-[1-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A44”)

Preparation as described for example 43 (steps 43.1-43.4). Yield: 33 mg(63%) colorless solid; LC/MS, Rt: 1.46 min; (M+H) 358.2; ¹H NMR (400MHz, DMSO-d₆) δ 7.86 (s, 1H), 7.56-7.49 (m, 2H), 7.42-7.33 (m, 2H),7.21-7.08 (m, 1H), 5.05-4.82 (m, 1H), 4.56-4.38 (m, 1H), 4.25-3.97 (m,1H), 3.93-3.68 (m, 1H), 2.82-2.57 (m, 2H), 1.66-1.43 (m, 3H).

Example 45(R)-1-[1-(4-Chloro-phenyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A45”)

Preparation as described for “A43” (steps 43.1-43.4). Yield: 39 mg (89%)colorless solid; LC/MS, Rt: 1.65 min; (M+H) 374.1; ¹H NMR (400 MHz,DMSO-d₆) δ 7.91 (s, 1H), 7.63-7.56 (m, 2H), 7.55-7.48 (m, 2H), 7.15 (s,1H), 5.03-4.41 (m, 2H), 4.27-3.68 (m, 2H), 2.85-2.61 (m, 2H), 1.67-1.47(m, 3H).

General reaction scheme for manufacturing compounds of formula Ia inwhich X═N, Y═N and R² denotes H

Example 46(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(1-phenyl-1,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-5-yl)-propan-1-one(“A46”)

46.1 (3-Nitro-pyridin-4-yl)-phenyl-amine

4-Chloro-3-nitro-pyridine (1.50 g; 9.177 mmol), aniline (1.02 mL; 11.013mmol) and anhydrous sodium acetate (3.76 g; 45.887 mmol) were suspendedin glacial acetic acid (7.50 mL) and stirred at 130° C. for 14 h. Themixture was cooled to room temperature and poured into water,neutralized with aqueous NaHCO₃-solution and extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (CombiFlashRF 200). Yield: 1.90 g (96%) yellowsolid; LC/MS, Rt: 1.40 min; (M+H) 216.1.

46.2 N4-Phenyl-pyridine-3,4-diamine

Compound 46.1 (2.30 g; 10.645 mmol) was hydrogenated at room temperaturein THF (30.0 mL) for 14 h using Pd—C(5%). The solution was filtered,evaporated to dryness and the residue was used in the next step withoutfurther purification. Yield: 1.91 g (97%) colorless solid; LC/MS, Rt:1.13 min; (M+H) 186.1.

46.3 1-Phenyl-1H-[1,2,3]triazolo[4,5-c]pyridine

Compound 46.2 (500.0 mg; 2.683 mmol) was dissolved in hydrochloric acid(40.3 mL; 4.025 mmol) and cooled to 0° C. Sodium nitrite (280.5 mg;4.025 mmol), dissolved in water (5.0 mL), was added slowly while acolorless precipitate was formed. The suspension was stirred at 0° C.for 30 min and then allowed to warm up to room temperature for 14 h. Thereaction mixture was diluted with saturated aqueous NaHCO₃-solution andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified by flash chromatography (CombiFlashRF200). Yield: 496 mg (94%) beige solid; LC/MS, Rt: 1.71 min; (M+H) 197.1.

46.4 1-Phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine

Compound 46.3 (299.0 mg; 1.524 mmol) was dissolved in methanol (10.0 mL)and hydrogenated over Pd—C(5%) at room temperature and 2.9-3.2 bar for14 h. The reaction was filtered and evaporated to dryness. Yield: 305 mg(100%) colorless oil; LC/MS, Rt: 0.89 min; (M+H) 201.1.

46.5(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(1-phenyl-1,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-5-yl)-propan-1-one(“A46”)

Acylation was performed as described for “A9” (step 9.4). Yield: 378 mg(72%) colorless solid; LC/MS, Rt: 1.88 min; (M+H) 341.1; ¹H NMR (400MHz, DMSO-d₆, 90° C.) δ 7.68-7.62 (m, 2H), 7.62-7.56 (m, 2H), 7.56-7.48(m, 1H), 6.97 (s, 1H), 4.92 (s, 2H), 4.16-4.04 (m, 1H), 4.04-3.94 (m,1H), 2.94 (t, J=5.7 Hz, 2H), 1.61-1.57 (m, 3H).

Example 47(R)-3,3,3-Trifluoro-1-[1-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A47”)

Preparation as described for “A46” (steps 46.1-46.5). Yield: 89 mg (70%)colorless solid; LC/MS, Rt: 1.93 min; (M+H) 359.0; ¹H NMR (400 MHz,DMSO-d₆, 90° C.) δ 7.78-7.61 (m, 2H), 7.49-7.34 (m, 2H), 6.97 (s, 1H),4.91 (s, br, 2H), 4.17-3.93 (m, 2H), 2.91 (t, J=5.7 Hz, 2H), 1.69-1.47(m, 3H).

Example 48(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propan-1-one(“A48”)

3-Phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (60.0 mg;0.300 mmol) was coupled with(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (52.1 mg; 0.330mmol) as described for “A9” (step 9.4). Yield: 78 mg (77%) colorlesssolid; LC/MS, Rt: 1.54 min; (M+H) 341.2; ¹H NMR (400 MHz, DMSO-d₆, 80°C.) δ 7.79-7.71 (m, 2H), 7.58-7.48 (m, 3H), 7.14 (s, 1H), 5.22-4.95 (m,2H), 4.33-4.03 (m, 4H), 1.60 (s, 3H).

Example 49(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl)-propan-1-one(“A49”)

3-Phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine (50.0 mg; 0.251 mmol)was coupled with (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid(43.6 mg; 0.276 mmol) as described for “A9” (step 9.4). Yield: 41 mg(49%) colorless solid; LC/MS, Rt: 1.36 min; (M+H) 340.2; ¹H NMR (400MHz, DMSO-d₆) δ 7.54-7.41 (m, 4H), 7.41-7.23 (m, 2H), 7.09 (s, 1H),5.37-3.84 (m, 6H), 1.59 (s, 3H).

General reaction scheme for manufacturing compounds of formula Ib inwhich X═N, Y═CH and R² denotes H

Example 50(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-5,6-dihydro-8H-imidazo-[1,5-a]pyrazin-7-yl)-propan-1-one(“A50”)

50.1 N-Pyrazin-2-ylmethyl-benzamide (Pyrazin-2-yl)methanamine (500.0 mg;4.353 mmol) was dissolved in dichloromethane (20.0 mL) under argon andcooled to 0° C. N-Ethyldiisopropylamine (0.89 mL; 5.223 mmol) was addedfollowed by the addition of benzoyl chloride (0.56 mL; 4.788 mmol). Thereaction mixture was allowed to warm to room temperature and stirred for18 h. The reaction mixture was diluted with saturated NaHCO₃ solution.The organic phase was separated and the aqueous layer was washed 3 timeswith dichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and evaporated to dryness. The residue was purified byflash chromatography (Companion RF; 40 g Si50 silica gel column). Yield:895 mg (96%) yellow solid; LC/MS, Rt: 1.36 min; (M+H) 214.1.

50.2 3-Phenylimidazo[1,5-a]pyrazine

N-Pyrazin-2-ylmethyl-benzamide (300.0 mg; 1.353 mmol) was dissolved indry acetonitrile (25.0 mL). POCl₃ (1.24 mL; 13.534 mmol) was added undernitrogen atmosphere and the reaction mixture was heated at 85° C. for 4h.

The reaction mixture was cooled to room temperature and evaporated todryness. The residue was diluted in a mixture of DCM, ice water andNaHCO₃ solution. The organic layer was separated and the aqueous layerwas extracted with dichloromethane. The combined organic layers weredried over sodium sulfate, filtered and evaporated to dryness. Yield:244 mg (92%) brown oil; LC/MS, Rt: 1.40 min; (M+H) 196.1.

50.3 3-Phenyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine

Compound 50.2 (244.0 mg; 1.249 mmol) was dissolved in methanol (10.0 mL)and hydrogenated over Pd—C(5%) at room temperature and 2.8 bar for 14 h.The reaction was filtered and evaporated to dryness. Yield: 233 mg (94%)yellow oil; LC/MS, Rt: 0.32 min; (M+H) 200.1.

50.4(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propan-1-one(“A50”)

Compound 50.3 (233.0 mg; 1.169 mmol) was coupled with(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (43.6 mg; 0.276mmol) as described for example 9 (step 9.4). Yield: 171 mg (43%)colorless solid; LC/MS, Rt: 1.25 min; (M+H) 340.1; ¹H NMR (400 MHz,DMSO-d₆, 90° C.) δ 7.73-7.68 (m, 2H), 7.51-7.45 (m, 2H), 7.44-7.39 (m,1H), 7.02 (s, 1H), 6.94-6.90 (m, 1H), 4.97 (s, 2H), 4.22 (t, J=5.3 Hz,2H), 4.18-4.05 (m, 2H), 1.66-1.58 (m, 3H).

Example 51(R)-3,3,3-Trifluoro-1-[3-(4-fluoro-phenyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-2-hydroxy-2-methyl-propan-1-one(“A51”)

Preparation as described for “A50” (steps 50.1-50.4). Yield: 234 mg(65%) colorless solid; LC/MS, Rt: 1.34 min; (M+H) 358.0; ¹H NMR (400MHz, DMSO-d₆, 90° C.) δ 7.73 (ddd, J=8.3, 5.3, 2.4 Hz, 2H), 7.27 (td,J=8.9, 2.1 Hz, 2H), 7.01 (s, 1H), 6.90 (s, 1H), 4.95 (s, 2H), 4.24-4.01(m, 4H), 1.61 (s, 3H).

General reaction scheme for manufacturing compounds of formula Ib inwhich X═N, Y═CH and R² denotes CH₃

Example 52(R)-3,3,3-Trifluoro-1-[(R)-3-(4-fluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-2-hydroxy-2-methyl-propan-1-one(“A52”)

Example 53(R)-3,3,3-Trifluoro-1-[(S)-3-(4-fluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-2-hydroxy-2-methyl-propan-1-one(“A53”)

52.1 2-Chloromethyl-6-methyl-pyrazine

To 2,6-dimethylpyrazine (500.0 mg; 4.623 mmol) and N-chlorosuccinimide(617.4 mg; 4.531 mmol) tetrachloromethane (12.5 mL) was added undernitrogen and the mixture was heated to reflux. Benzoylbenzenecarbo-peroxoate (22.2 mg; 0.077 mmol) was added and the colorlesssuspension was heated at 85° C. for 3 h. N-chlorosuccinimide (61.7 mg;0.453 mmol) was added and the reaction was heated for another 2 h andthen stirred at room temperature for 14 h. The reaction was diluted withwater and extracted with dichloromethane. The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography (CombiFlashRF 200). Yield:328 mg (51%) colorless oil;

LC/MS, Rt: 1.35 min; (M+H) 143.1/145.1.

52.2 2-(6-Methyl-pyrazin-2-ylmethyl)-isoindole-1,3-dione

Compound 52.1 (310.0 mg; 2.174 mmol), sodium hydrogen carbonate (219.0mg; 2.609 mmol) and phthalimide potassium salt (403.0 mg; 2.174 mmol)was dissolved in DMF (4.0 mL) and the dark red/brown solution wasstirred at room temperature for 14 h. The mixture was concentrated,diluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by flashchromatography (CombiFlashRF). Yield: 226 mg (41%) colorless solid;LC/MS, Rt: 1.74 min; (M+H) 254.1.

52.3 C-(6-Methyl-pyrazin-2-yl)-methylamine

To a suspension of 2-(6-methyl-pyrazin-2-ylmethyl)-isoindole-1,3-dione(1.57 g; 6.191 mmol) in ethanol (60.0 mL) hydrazinium hydroxide (2.41mL; 49.531 mmol) was added slowly while stirring and the mixture washeated to 80° C. After 5 min a colorless solution was formed whichturned into a colorless suspension after 30 min. The reaction mixturewas refluxed for further 6 h, cooled to room temperature, diluted withwater (80 mL) and 0.1 N NaOH (30 mL) and extracted with a mixture ofdichloromethane-methanol (1/1). The combined organic layers were driedover sodium sulfate, filtered and concentrated in vacuo. Yield: 417 mg(55%) colorless oil; LC/MS, Rt: 0.33 min; (M+H) 124.2.

52.4 4-Fluoro-N-(6-methyl-pyrazin-2-ylmethyl)-benzamide

Compound 52.3 (416.0 mg; 3.378 mmol) was dissolved in dichloromethane(15.0 mL) and cooled in an ice bath. N-ethyldiisopropylamine (0.69 mL;4.053 mmol) and 4-fluorobenzoyl chloride (0.43 mL; 3.547 mmol) wereadded and the ice bath was removed. A yellow solution was formed andstirred for 4 h. The mixture was diluted with saturated aqueousNaHCO₃-solution and water. The organic phase was separated and theaqueous layer was washed with dichloromethane. The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo. The crude product was purified by flash chromatography(CombiFlashRF 200). Yield: 728 mg (88%) yellow solid; LC/MS, Rt: 1.56min; (M+H) 246.1.

52.5 3-(4-Fluoro-phenyl)-5-methyl-imidazo[1,5-a]pyrazine

Compound 52.4 (728.0 mg; 2.967 mmol) was dissolved in dry acetonitrile(40.1 mL). POCl₃ (2.77 mL; 29.669 mmol) was added. The orange mixturewas stirred at 95° C. for 18 h. The reaction mixture was cooled to roomtemperature, cautiously diluted with water (150 mL) and neutralized withsodium bicarbonate. The organic phase was separated and the aqueouslayer was washed with dichloromethane. The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo. The cruderesidue was purified by flash chromatography (CombiFlashRF 200). Yield:617 mg (91%) yellow solid; LC/MS, Rt: 1.47 min; (M+H) 228.1.

52.63-(4-Fluoro-phenyl)-5-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine

Compound 52.5 (617.0 mg; 2.713 mmol) was dissolved in methanol (10.0 mL)and hydrogenated over Pd—C(5%) at room temperature and 3.0 bar for 4 h.The reaction was filtered and evaporated to dryness. Yield: 606 mg (97%)off-white oil; LC/MS, Rt: 0.34 min; (M+H) 232.2.

52.7(R)-3,3,3-Trifluoro-1-[3-(4-fluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-2-hydroxy-2-methyl-propan-1-one

Compound 52.6 (606.0 mg; 2.619 mmol) was coupled with(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid as described forexample 9 (step 9.4).

Yield: 576 mg (59%) yellow oil

The preparative separation of the diastereomers (“A52” and “A53”) wasperformed by SFC (column: ChiralPak AD-H; eluent: CO₂:methanol—80:20).

The combined fractions were evaporated to dryness.

“A52”: 58 mg colorless solid; LC/MS, Rt: 1.45 min; (M+H) 372.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.76-7.68 (m, 2H), 7.32-7.24 (m, 2H), 7.03(s, 1H), 6.92 (s, 1H), 5.51-5.23 (m, 1H), 4.81-4.72 (m, 1H), 4.63 (d,J=16.5 Hz, 1H), 4.55 (d, J=13.7 Hz, 1H), 3.63-3.53 (m, 1H), 1.60 (s,3H), 1.08 (d, J=6.5 Hz, 3H).

“A53”: 57 mg colorless solid; LC/MS, Rt: 1.43 min; (M+H) 372.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.74-7.67 (m, 2H), 7.31-7.22 (m, 2H), 6.98(s, 1H), 6.86 (s, 1H), 5.43-5.16 (m, 1H), 4.80-4.72 (m, 1H), 4.64 (d,J=16.4 Hz, 1H), 4.51-4.44 (m, 1H), 3.59 (d, J=12.1 Hz, 1H), 1.58 (s,3H), 1.08 (d, J=6.5 Hz, 3H).

Example 54(R)-1-[(R)-3-(2,4-Difluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A54”)

Example 55(R)-1-[(S)-3-(2,4-Difluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A55”)

Preparation as described for “A52”/“A53” (steps 52.4-52.7). Thepreparative separation of the diastereomers was performed by SFC(column: ChiralPak AD-H; eluent: CO₂:ethanol—88:12). The combinedfractions were evaporated to dryness.

“A54”: 333 mg colorless solid; LC/MS, Rt: 1.44 min; (M+H) 390.2; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.62-7.50 (m, 1H), 7.30 (td, J=10.2, 2.5Hz, 1H), 7.18 (td, J=8.4, 2.3 Hz, 1H), 7.03 (s, 1H), 6.89 (s, 1H), 5.34(br, 1H), 4.68 (d, J=16.3 Hz, 1H), 4.51-4.32 (m, 2H), 3.62 (d, J=11.8Hz, 1H), 1.59 (s, 3H), 0.99 (d, J=6.3 Hz, 3H).

“A55”: 342 mg colorless solid; LC/MS, Rt: 1.42 min; (M+H) 390.2; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 7.67-7.46 (m, 1H), 7.30 (td, J=10.2, 2.5Hz, 1H), 7.18 (td, J=8.5, 2.4 Hz, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 5.29(br, 1H), 4.69 (d, J=16.5 Hz, 1H), 4.46-4.31 (m, 2H), 3.66 (d, J=10.1Hz, 1H), 1.58 (s, 3H), 1.00 (d, J=6.4 Hz, 3H).

Example 56(R)-1-[(S)-3-(3,5-Difluoro-pyridin-2-yl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A56”)

Example 57(R)-1-[(R)-3-(3,5-Difluoro-pyridin-2-yl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A57”)

Preparation as described for “A52”/“A53” (steps 52.4-52.7). Thepreparative separation of the diastereomers was performed by SFC(column: ChiralPak AD-H; eluent: CO₂:ethanol (containing 0.5%diethylamine)—88:12). The combined fractions were evaporated to dryness.

“A56”: 333 mg colorless solid; LC/MS, Rt: 1.43 min; (M+H) 391.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.54 (s, 1H), 8.04-7.82 (m, 1H), 7.11-6.90(m, 2H), 5.35 (s, br, 1H), 5.15-5.01 (m, 1H), 4.70 (d, J=16.8 Hz, 1H),4.49 (d, J=13.6 Hz, 1H), 3.60 (d, J=12.4 Hz, 1H), 1.62-1.56 (m, 3H),1.17 (d, J=6.5 Hz, 3H).

“A57”: 342 mg colorless solid; LC/MS, Rt: 1.45 min; (M+H) 391.1; ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ 8.54 (d, J=2.3 Hz, 1H), 7.99-7.87 (m, 1H),7.04 (s, 1H), 6.95 (s, 1H), 5.41 (s, br, 1H), 5.17-5.00 (m, 1H), 4.68(d, J=16.7 Hz, 1H), 4.56 (d, J=13.9 Hz, 1H), 3.55 (d, J=12.8 Hz, 1H),1.61 (s, 3H), 1.17 (d, J=6.4 Hz, 3H).

Pharmacological Data

TABLE 1 Inhibition of PDHK of some representative compounds of theformula Ia or Ib Compound IC₅₀ PDHK2 Binding (ITC) IC₅₀ No. (enzymeassay) KD (cell data) “A1” A A C “A2” C B “A3” A A B “A4” A A B “A5” A AB “A6” B A C “A7” A A B “A8” B B C “A9” A A A “A10” A A A “A11” C B B“A12” A A A “A13” B B C “A14” A A A “A15” B B “A16” A A A “A17” B B B“A18” A A A “A19” B B “A20” A A A “A21” B “A22” A A A “A23” C “A24” A AA “A25” B “A26” C “A27” B “A28” B A C “A29” B B “A30” A A A “A31” C“A32” A A A “A33” C “A34” A A A “A35” B “A36” B “A37” B B C “A38” A A A“A39” B “A40” A A A “A41” C “A42” B A “A43” B A B “A44” B A C “A45” B AC “A46” B A C “A47” B A C “A48” B A “A49” B A C “A50” B A C “A51” B A C“A52” A A A “A53” C “A54” A A A “A55” B “A56” C “A57” B A A IC₅₀: <0.3μM = A 0.3-3 μM = B 3-50 μM = C

The compounds shown in Table 1 are preferred compounds according to theinvention.

Particularly preferred compounds are 14, 20, 34, 38, 40, 54 and 57.

The following examples relate to medicaments:

Example A: Injection Vials

A solution of 100 g of an active ingredient of the formula Ia or Ib and5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula Ia or Ib with100 g of soya lecithin and 1400 g of cocoa butter is melted, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

Example C: Solution

A solution is prepared from 1 g of an active ingredient of the formulaIa or Ib, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of an active ingredient of the formula Ia or Ib are mixed with99.5 g of Vaseline under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of active ingredient of the formula Ia or Ib, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

Example F: Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G: Capsules

2 kg of active ingredient of the formula Ia or Ib are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H: Ampoules

A solution of 1 kg of active ingredient of the formula Ia or Ib in 60 lof bidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula Ia or of the formula Ib

in which X denotes CH or N, Y denotes CH or N, R¹ denotes H, A,(CH₂)—Ar, (CH₂)_(n)Het or Cyc, R² denotes H or CH₃, Ar denotes phenyl,which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstitutedby Hal, A, CN, OA, [C(R⁵)₂]_(p)OH, [C(R⁵)₂]_(p)N(R⁵)₂, NO₂,[C(R⁵)₂]_(p)COOR⁵, NR⁵COA, NR⁵SO₂A, [C(R⁵)₂]_(p)SO₂N(R⁵)₂, S(O)_(p)A,O[C(R⁵)₂]_(m)N(R⁵)₂, NR⁵COOA, NR⁵CON(R⁵)₂ and/or COA, Het denotes amono- or bicyclic saturated, unsaturated or aromatic heterocycle having1 to 4 N, O and/or S atoms, which is unsubstituted or mono- ordisubstituted by Hal, A, CN, OA, [C(R⁵)₂]_(p)OH, [C(R⁵)₂]_(p)N(R⁵)₂,NO₂, [C(R⁵)₂]_(p)COOR⁵, NR⁵COA, NR⁵SO₂A, [C(R⁵)₂]_(p)SO₂N(R⁵)₂,S(O)_(p)A, O[C(R⁵)₂]_(m)N(R⁵)₂, NR⁵COOA, NR⁵CON(R⁵)₂ and/or COA, Cycdenotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, which isunsubstituted or monosubstituted by OH, A denotes unbranched or branchedalkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/orCH₂-groups may be replaced by N-, O- and/or S-atoms and/or wherein 1-7H-atoms may be replaced by R⁴, R⁴ denotes F, Cl or OH, R⁵ denotes H oderA′, A′ denotes unbranched or branched alkyl with 1-6 C-atoms, wherein1-5 H-atoms may be replaced by F, Hal denotes F, Cl, Br or I, m denotes1, 2, 3 or 4, n denotes 0, 1 or 2, p denotes 0, 1, 2, 3 or 4, with theproviso that, if X═CH then Y═N or if Y═CH then X═N, and pharmaceuticallyacceptable salts, tautomers and stereoisomers thereof, includingmixtures thereof in all ratios.
 2. Compounds according to claim 1, inwhich Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,tetra- or pentasubstituted by Hal, A, CN and/or OA, and pharmaceuticallyacceptable salts, tautomers and stereoisomers thereof, includingmixtures thereof in all ratios.
 3. Compounds according to claim 1, inwhich Het denotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl,piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl orthiadiazolyl, each of which is unsubstituted or mono- or disubstitutedby Hal, A and/or OA, and pharmaceutically acceptable salts, tautomersand stereoisomers thereof, including mixtures thereof in all ratios. 4.Compounds according to claim 1 in which X denotes CH or N, Y denotes CHor N, R¹ denotes H, A, (CH₂)—Ar, (CH₂)_(n)Het or Cyc, R² denotes H orCH₃, Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,tetra- or pentasubstituted by Hal, A, CN and/or OA, Het denotespyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl,pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl,oxazolyl, isoxazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each ofwhich is unsubstituted or mono- or disubstituted by Hal, A and/or OA,Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, which isunsubstituted or monosubstituted by OH, A denotes unbranched or branchedalkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/orCH₂-groups may be replaced by N-, O- and/or S-atoms and/or wherein 1-7H-atoms may be replaced by R⁴, R⁴ denotes F, Cl or OH, Hal denotes F,Cl, Br or I, n denotes 0, 1 or 2, with the proviso that, if X═CH thenY═N or if Y═CH then X═N, and pharmaceutically acceptable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 5. Compounds according to claim 1, selected from the group No.Name “A1”(2R)-1-[1-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A2”(2R)-1-[2-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A3”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(1-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one “A4”(R)-3,3,3-Trifluoro-1-[1-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one“A5” (R)-1-[1-(2,4-Difluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A6”(R)-1-[2-(2,4-Difluoro-phenyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A7”(R)-1-(1-tert-Butyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A8”(R)-1-(2-tert-Butyl-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A9”(2R)-1-[1-(4-chlorophenyl)-7-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A10”(R)-1-[(R)-1-(4-Chloro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A11”(R)-1-[(S)-1-(4-Chloro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A12”(2R)-3,3,3-trifluoro-1-[1-(4-fluorophenyl)-7-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one “A13”(2R)-3,3,3-trifluoro-1-[2-(4-fluorophenyl)-7-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one “A14”(R)-3,3,3-Trifluoro-1-[(R)-1-(4-fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan- 1-one“A15” (R)-3,3,3-Trifluoro-1-[(S)-1-(4-fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan- 1-one“A16” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(7-methyl-1-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one “A17”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(7-methyl-2-phenyl-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one “A18”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-((R)-7-methyl-1-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one “A19”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-((S)-7-methyl-1-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one “A20”(R)-1-[(R)-1-(2,4-Difluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A21”(R)-1-[(S)-1-(2,4-Difluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A22”(R)-1-((R)-1-tert-Butyl-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A23”(R)-1-((S)-1-tert-Butyl-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A24”(R)-3,3,3-Trifluoro-1-[(R)-1-(2-fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan- 1-one“A25” (R)-3,3,3-Trifluoro-1-[(S)-1-(2-fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan- 1-one“A26” 2-[(R)-7-Methyl-5-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]- benzonitrile“A27” 2-[(S)-7-Methyl-5-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]- benzonitrile“A28” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-((R)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one “A29”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-((S)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propan-1-one “A30”(R)-3,3,3-Trifluoro-2-hydroxy-1-[(R)-1-(6-methoxy-pyridin-3-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one “A31”(R)-3,3,3-Trifluoro-2-hydroxy-1-[(S)-1-(6-methoxy-pyridin-3-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one “A32”(R)-3,3,3-Trifluoro-1-[(R)-1-(3-fluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one “A33”(R)-3,3,3-Trifluoro-1-[(S)-1-(3-fluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one “A34”(R)-1-[(R)-1-(3,5-Difluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A35”(R)-1-[(S)-1-(3,5-Difluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A36”(R)-3,3,3-Trifluoro-1-[(R)-1-(5-fluoro-2-methoxy-pyrimidin-4-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one “A37”(R)-3,3,3-Trifluoro-1-[(S)-1-(5-fluoro-2-methoxy-pyrimidin-4-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one “A38”(R)-3,3,3-Trifluoro-2-hydroxy-1-[(R)-1-(4-hydroxy-cyclohexyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one “A39”(R)-3,3,3-Trifluoro-2-hydroxy-1-[(S)-1-(4-hydroxy-cyclohexyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one “A40”(R)-3,3,3-Trifluoro-1-[(R)-1-(5-fluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl- propan-1-one“A41” (R)-3,3,3-Trifluoro-1-[(S)-1-(5-fluoro-pyridin-2-yl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one “A43”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-propan-1-one “A44”(R)-3,3,3-Trifluoro-1-[1-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one “A45”(R)-1-[1-(4-Chloro-phenyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A46”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(1-phenyl-1,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-5-yl)-propan-1-one “A47”(R)-3,3,3-Trifluoro-1-[1-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-[1,2,3]triazolo[4,5-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one“A48” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propan-1-one “A49”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl)-propan-1-one “A50”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(3-phenyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propan-1-one “A51”(R)-3,3,3-Trifluoro-1-[3-(4-fluoro-phenyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-2-hydroxy-2-methyl-propan-1-one “A52”(R)-3,3,3-Trifluoro-1-[(R)-3-(4-fluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-2-hydroxy-2-methyl- propan-1-one“A53” (R)-3,3,3-Trifluoro-1-[(S)-3-(4-fluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-2-hydroxy-2-methyl- propan-1-one“A54” (R)-1-[(R)-3-(2,4-Difluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A55”(R)-1-[(S)-3-(2,4-Difluoro-phenyl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A56”(R)-1-[(S)-3-(3,5-Difluoro-pyridin-2-yl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A57”(R)-1-[(R)-3-(3,5-Difluoro-pyridin-2-yl)-5-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

and pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 6. Process for thepreparation of compounds of the formula Ia or Ib according to claim 1and pharmaceutically acceptable salts, tautomers and stereoisomersthereof, characterised in that a compound of the formula IIa or IIb

in which X, Y, R¹ and R² have the meanings indicated in claim 1, isreacted with a compound of the formula III

in which L denotes Cl, Br, I or a free or reactively functionallymodified OH group, and/or a base or acid of the formula Ia or Ib isconverted into one of its salts.
 7. Medicaments comprising at least onecompound of the formula Ia or Ib according to claim 1 and/orpharmaceutically acceptable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios, and optionally anpharmaceutically acceptable carrier, excipient or vehicle.
 8. Compoundsof the formula Ia or Ib according to claim 1 and pharmaceuticallyacceptable salts, tautomers and stereoisomers thereof, includingmixtures thereof in all ratios, for the use for the treatment and/orprevention of cancer, diabetes, heart ischemia, insulin resistancesyndrome, metabolic syndrome, hyperglycemia, dyslipidemia,atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia,hyperlactacidemia, mitochondrial disease, mitochondrialencephalomyopathy.
 9. Compounds according to claim 8 for the use for thetreatment and/or prevention of diseases selected from the group cancerof head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx,chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder,uterine, cervix, breast, ovaries, testicles or other reproductiveorgans, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas,brain, central nervous system, solid tumors and blood-borne tumors. 10.Medicaments comprising at least one compound of the formula Ia or Ibaccording to claim 1 and/or pharmaceutically acceptable salts, tautomersand stereoisomers thereof, including mixtures thereof in all ratios, andat least one further medicament active ingredient.
 11. Set (kit)consisting of separate packs of (a) an effective amount of a compound ofthe formula Ia or Ib according to claim 1 and/or pharmaceuticallyacceptable salts, tautomers and stereoisomers thereof, includingmixtures thereof in all ratios, and (b) an effective amount of a furthermedicament active ingredient.
 12. The compound1-[(R)-1-(4-Fluoro-phenyl)-7-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-hydroxy-2-methyl-propan-1-one(“A42”) and pharmaceutically acceptable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios.